Prognosis for children and young adults with metastatic, relapsed, or refractory solid tumors remains unacceptably poor and has not improved significantly over the past three decades despite multimodality treatment including surgery, radiation, and chemotherapy. Current approaches have reached the limits of maximal dose intensification, and the acute and late effects of combination therapy are substantial. The goal of this proposal is to improve the cure rate and quality of life in pediatric cancer patients through approaches that maximize effects of current therapy while minimizing associated complications. Magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) provides controlled delivery of heat through precise image guidance, real-time temperature mapping, and spatially well-defined deposition of energy using an external applicator that is completely non-invasive and non-ionizing. Lyso-thermosensitive liposomal doxorubicin (LTLD) is a heat-activated formulation of liposomal doxorubicin with the unique property of heat-activated release of doxorubicin, an active agent in most pediatric solid tumors. The flexibility and control over low temperature local heating induced by MR-HIFU provides an ideal system to be used in conjunction with LTLD. The synergistic effects of this therapy are manifold and include enhanced permeability of the tumor vasculature, enhanced extravasation of the drug and subsequent high concentrations of doxorubicin in the targeted tumor, the expression of heat shock proteins, inhibition of DNA repair, and stimulation of immune responses. We propose a phase 1 trial of LTLD combined with MR-HIFU induced mild hyperthermia (HT) in children and young adults with refractory or relapsed solid tumors. We will 1) determine the maximum tolerated dose, toxicity profile, and pharmacokinetics of LTLD, 2) determine the feasibility, accuracy and precision of the MR- HIFU algorithm for sustaining large volume mild HT, and 3) determine the changes in biomarkers of adaptive immunity and tumor derived microvesicles in children and young adults treated with LTLD and MR-HIFU induced mild HT and correlate with response in target and off target lesions. The proposed clinical research represents the first assessment of LTLD in children with refractory solid tumors and the first assessment of MR-HIFU induced mild HT. The ability to preferentially expose tumors to high local concentration of doxorubicin without increasing systemic side effects in conjunction with the spatial accuracy and precise treatment planning based on real-time imaging and temperature monitoring, lack of ionizing radiation, and non-invasive nature of MR-HIFU make this drug-device combination an extremely attractive modality. This novel approach can be readily incorporated into existing treatment regimens for both newly diagnosed and recurrent solid tumors, potentially transforming the way we treat children with cancer.